It has been known that, in organisms such as typically mammals, histamine that is a physiologically-active endogenous factor functions as a neurotransmitter and has extensive pharmacological activities (for example, see Life Science, 17, 1975, 503 (1975)). Immunohistochemical studies have made it clear that a histamine-agonistic (producing) cell body exists in the nodal papillary nucleus in a posterior hypothalamic region and that histamine nerve fibers project histamine in an extremely broad range in the brain, which supports various pharmacological effects of histamine (for example, see Journal of Comprehensive Neurology, 273, 283). The existence of histamine-agonistic nerves in the nodal papillary nucleus in a posterior hypothalamic region suggests that histamine may have an important role in control of physiological functions relating to brain functions, especially to hypothalamic functions (sleep, vigilance rhythm, incretion, eating and drinking action, sexual action, etc.) (for example, see Progress in Neurobiology, 63, 637 (2001)). The existence of histamine projection to the brain region that relates to vigilance sustenance, for example, to cerebral cortex suggests the role of histamine in control of vigilance or vigilance-sleep cycle. The existence of histamine projection to many peripheral structures such as hippocampus and amygdaloid complex suggests the role of histamine in control of autonomic nerves, emotion, control of motivated action and learning/memory process.
On the other hand, when released from producing cells, histamine acts with a specific polymer that is referred to as a receptor on the surface of a cell membrane or inside a target cell, therefore exhibiting its pharmacological effects for control of various body functions. Heretofore, four types of histamine receptors (H1 to H4) have been found. In particular, the presence of a histamine receptor that participates in the central and peripheral nervous functions, a histamine-H3 receptor, has been shown by various pharmacological and physiological studies (for example, see Trends in Pharmacological Science, 8, 24 (1986)); and recently, human and rodent histamine-H3 receptor genes have been identified and their existence has been made clear (for example, see Molecular Pharmacology, 55, 1101 (1999)). It is shown that a histamine-H3 receptor exists in the presynaptic membrane of central or peripheral neurocytes and functions as a self-receptor, therefore controlling the liberation of histamine and controlling the release of other neurotransmitters. Specifically, it is reported that a histamine-H3 receptor agonist, or its antagonist or inverse-agonist (generically referred to as antagonist) controls the release of histamine, noradrenaline, serotonin, acetylcholine or dopamine from nerve ending. For example, the release of these neurotransmitters is inhibited by an agonist such as (R)-(α)-methylhistamine, and the release of these neurotransmitters is promoted by an antagonist or inverse-agonist such as thioperamide (for example, see Trends in Pharmacological Science, 19, 177 (1998)). Recent studies have shown that a histamine-H3 receptor has extremely high homeostatic activities (endogenous agonistic factor, e.g., activity observed in the absence of histamine) in the receptor-expressing cells/tissues or in a membrane fraction derived from the expressing cells/tissues and even in living bodies (for example, see Nature, 408, 860). It is reported that these homeostatic activities are inhibited by an antagonist or an inverse-agonist. For example, a homeostatic self-receptor activity is inhibited by thioperamide or syproxyfan, and, as a result, the release of neurotransmitters from nerve ending, for example, the release and liberation of histamine from it is thereby promoted.
Various studies have been made for clarifying the effects of a histamine-H3 receptor. In animal experiments with rats, a high-level selective inhibitor of histamine synthase (histidine decarboxylase) inhibits the vigilance of rats, which suggests that a histamine-H3 receptor may function for controlling motive vigilance. Administration of a histamine-H3 receptor agonist, (R)-(α)-methylhistamine to cats increases their deep slow-wave sleep (for example, see Brain Research, 523, 325 (1990)). Contrary to this, it has been clarified that a histamine-H3 receptor antagonist or inverse-agonist, thioperamide dose-dependently increases vigilance, and decreases slow-wave and REM sleep (see Science, 48, 2397 (1991)). This suggests that a histamine-H3 receptor may participate in control of vigilance-sleep, and suggests a possibility that a selective histamine-H3 receptor agonist, or its antagonist or inverse-agonist may be useful for treatment of sleep disorders. Further, in animal experiments with rats, administration of histamine to the ventricle of rats inhibited their eating action, therefore suggesting that histamine may participate in control of eating action (for example, see Research, 793, 279 (1998)), and it has been clarified that thioperamide dose-dependently inhibits eating action and promotes intracerebral histamine liberation (for example, see Life Science, 69, 469 (2001)). These informations suggest that a histamine-H3 receptor may participate in eating action control, further suggesting a possibility that an a histamine-H3 receptor antagonist or inverse-agonist may be useful for prevention or remedy of metabolic diseases such as eating disorder, obesity, diabetes, emaciation, hyperlipemia. In addition, in animal experiments with rats, it has been clarified that administration of a histamine-H3 receptor agonist, (R)-(α)-methylhistamine to rats dose-dependently lowered their basal diastolic pressure, and its action was antagonized by a histamine-H3 receptor antagonist or inverse-agonist, thioperamide (for example, see Journal of Physiology and Pharmacology, 49, 191 (1998)). These informations suggest that a histamine-H3 receptor may participate in control of blood pressure, heart beat and cardiac output, further suggesting a possibility that a histamine-H3 receptor agonist or its antagonist or inverse-agonist may be useful for prevention or remedy of circulatory system diseases such as hypertension and various cardiac disorders.
It is reported that, in animal experiments with rats, administration of a histamine-H3 receptor agonist, (R)-(α)-methylhistamine to rats lowered their object recognition and learning effects in the object recognition test and the passive turnout test with them, while on the other hand, in the scopolamine-induced amnesia test with them, a histamine-H3 receptor antagonist or inverse-agonist, thioperamide dose-dependently relieved their amnesia induced by the chemical (for example, see Behavioural Brain Research, 104, 147 (1999)). These informations suggest a possibility that a histamine-H3 receptor antagonist or inverse-agonist may be useful for prevention or remedy of various diseases accompanied by memory and learning disorder, for example, Alzheimer's disease, Parkinson's disease or attention deficit/hyperactivity disorder. Further, it has been clarified that, in animal experiments with rats, a histamine-H3 receptor antagonist or inverse-agonist, thioperamide dose-dependently inhibited the spasm induced by electric shock or the epileptoid seizure induced by pentylene tetrazole (PTZ) (for example, see European Journal of Pharmacology, 234, 129 (1993) and Pharmacology, Biochemistry and Behavior, 68, 735 (2001)). These informations suggest a possibility that a histamine-H3 receptor antagonist or inverse-agonist may be useful for prevention or remedy of epilepsy or central spasm. In addition, a histamine-H3 receptor antagonist or inverse-agonist, thioperamide or GT-2331 reduces emotional cataplexy and sleep of narcoleptic dogs (for example, see Brain Research, 793, 279 (1998)).
These information suggest that an H3 receptor may participate in control of vigilance-sleep and sleep disorder-associated diseases, further suggesting a possibility that a selective histamine-H3 agonist or its antagonist or inverse-agonist may be useful for treatment of sleep disorders or various sleep disorder-associated diseases (for example, idiopathic hypersomnia, repetitive hypersomnia, true hypersomnia, narcolepsy, sleep periodic acromotion disorder, sleep apnea syndrome, circadian rhythm disorder, chronic fatigue syndrome, REM sleep disorder, senile insomnia, night worker sleep insanitation, idiopathic insomnia, repetitive insomnia, true insomnia, melancholia, schizophrenia).
In animal experiments with rats, administration of a histamine-H3 receptor antagonist or inverse-agonist, thioperamide or GT-2331 to rats relieved the condition of learning disorder (LD) and attention deficit hyperactivity disorder (ADHD) (for example, see Life Science, 69, 469 (2001)).
These informations suggest a possibility that a selective H3-agonist or its antagonist or inverse-agonist may be useful for remedy and/or prevention of learning disorder or attention deficit hyperactivity disorder.
There are known a novel imidazole derivative (for example, see JP-T 10-501001) as a histamine-H3 receptor antagonist and/or agonist; 4-(4(5)-imidazolyl)butyramidine, 2-(4)-imidazolylethylisothiourea or an N-methyl derivative thereof having an antagonistic activity against a histamine-H3 receptor (for example, see JP-A-6-87742), or a migraine remedy, a tranquilizer, a hypnotic, an anesthetic, a sedative, an anxiolytic, an antiasthmatic, an antibronchitic and an antiinflammatory agent that comprise N-methyl derivative thereof; and a histamine receptor antagonist useful for remedy of allergic rhinitis, inflammatory intestinal disorders, asthma, bronchitis and vomition that comprises an N-methyl-N-(4-piperidin-1-yl)-2-arylbutyl)benzamide (for example, see JP-T-2002-504082).
However, no one knows that a piperidine derivative having a skeleton with a nitrogen-containing cyclo-ring and a specific nitrogen-containing heteroaryl ring or phenyl group bonding to piperidine could be a histamine-H3 antagonist, and no one also knows that the piperidine derivative could be effective for metabolic system diseases, circulatory system diseases, central or peripheral nervous system diseases, and especially effective for relieving obesity.